Undefined/Nonmalignant Hepatic Nodules and HCC Post-DAA Treatment for HCV

Inpatients with hepatitis C (HCV) receiving direct-acting antivirals (DAA), an early high incidence of de novo hepatocellular carcinoma(HCC) in those with undefined/non-malignant liver nodules (UNMN) and recurrentHCC, were observed.

Inpatients with hepatitis C (HCV)receiving direct-acting antivirals (DAA), an early high incidence of de novo hepatocellular carcinoma(HCC) in those with undefined/non-malignant liver nodules (UNMN) and recurrent HCC, were observed, though it was not accompanied by increased tumor aggressiveness. This according to results from a prospective multicenter study published in the Journal of Hepatology.

Previous work has reported unexpected early increases in incidence, recurrence and clinical aggressiveness of HCCin HCV cirrhotic patients after treatment with DAA, however, other studies have contradicted these findings. In order to clarify the controversy, investigators enrolled 2 patient groups, 1161 patients without HCC (group 1) and 124 patients with cirrhosis who had received a curative treatment for an HCC (group 2). Clinical features of these groups were analyzed with respect to HCC incidence and recurrence.

Median study time for group 1 and 2 respectively were, 17 and 16 months. During this time, de novo HCC developed in 48 patients (yearly incidence 3.1 per 100 person-years) and recurred in 40 (mean yearly incidence 29.9 per 100 person-years). In group 1, a peak of HCC instant incidence was observed at 4.2 months for patients with undefined/non-malignant liver nodules. This was observed to be 7.7 months in group 2.

Undefined/non-malignant liver nodules (hazard ratio [HR], 3.11;95% CI, 1.47-6.57;P =.003), ascites detected any time before enrolment (HR, 3.04, 95% CI, 1.23-7.51;P=.02) and alpha-fetoprotein (AFP) log-value (HR, 1.90; 95% CI, 1.05-3.44;P =.03), were the variables independently associated with the incidence of de novo HCC using multivariable Cox regression. Variables associated with HCC recurrence were history of alcohol abuse (HR, 2.10; 95% CI, 1.08-4.09;P =.03) and history of recurrence of HCC (HR, 2.87; 95% CI, 1.35-6.09;P=.006).

Intention-to-treat analysis analysis showed that sustained virologic response was demonstrated in 1119 (96%) patients in group 1 and in 118 (95%) in group 2 (P = .50).

Investigators acknowledged a potential weakness of the study might be, “an overestimation of the radiological complete response to HCC treatment and the impossibility to fully prevent to disentangle cases of early HCCdue to misclassification from those related to rapid growth of nests of liver cancer cells.” However, the study was strengthened by, “the prospective enrolment of patients with advanced fibrosis lacking vital cancer cells, the participation of centers with expertise in management of HCC, the standardized criteria for antiviral therapy with second and third wave of DAAand overall the centralized revision of all CT/MRI images to try to do our best in avoiding misclassification.”

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Investigators concluded that the results of this work suggest a time dependent relationship between de novo appearance of HCC and the presence of undefined/non-malignant liver nodules detected before the beginning of DAA treatment. They were unable to answer however, whether patients with undefined/non-malignant liver nodules includes those with a clinically undetectable nests of cancer cells or with precancerous lesions progressing to HCC upon DAA treatment, as no direct relationship between DAA and HCC development was demonstrated.


Sangiovanni A, Alimenti E, Gattai R, et al. Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis [published online March 31 2020]. J Hepatol. doi:10.1016/j.jhep.2020.03.030